# ICOSL Signaling in Macrophages Promotes Anti-Tumor Immunity

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $43,992

## Abstract

Project Summary/Abstract:
Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease for which there are few long-term survivors.
The inflammatory tumor microenvironment (TME) is known to influence pancreatic cancer progression by
either generating cytotoxic T cell responses, or, more commonly, by inducing tumor-permissive tolerance.
Many studies have shown that tumor-associated macrophages, or TAMs, play a vital role in educating T cells
toward immunogenic or tolerogenic differentiation in PDA. However, the mechanisms that regulate
macrophage phenotype in this disease are not well understood. ICOSL, the cognate ligand for the ICOS co-
stimulatory receptor on T cells, is a B7-family 40 kD protein expressed on macrophages. While ICOS signaling
has been well-characterized, the concept of ICOSL ‘back-signaling’ into macrophages upon engagement by
ICOS has not been well described. My preliminary work indicates that ICOSL is up-regulated on tumor
associated macrophages in the context of pancreatic cancer. Genetic deletion or antibody-mediated
neutralization of ICOSL on macrophages results in their differentiation toward an alternatively activated M2-like
phenotype and acceleration of cancer progression. Conversely, I found that ICOSL engagement or activation
in macrophages by treatment with an ICOS Fc leads to a profound immunogenic program in vitro. Mass
spectrometric analysis has shown that ICOSL co-precipitates with STAT1 in macrophages, a known driver of
M1-like phenotype. However, the specific molecular mechanisms through which ICOSL acts as a regulator of
macrophage phenotype and its applicability as a master regulator of anti-tumor immunity in PDA remains
unknown.
My proposal will attempt to bridge this gap in knowledge through two main specific aims: Aim 1 will seek to
determine if ICOSL-mediated tumor protection in PDA is a T-cell dependent phenomenon. Specifically, this aim
will explore the effects of ICOSL-activation or neutralization in macrophages on T-cell phenotype; employing
flow cytometry, antigen presentation assays, and 10x single cell RNA sequencing of intra-tumoral immune cells
from multiple murine models of PDA. Aim 2 will seek to address the specific intracellular signaling mechanisms
through which ICOSL regulates macrophage polarization. By employing site directed mutagenesis to map the
interaction surface that mediates ICOSL binding to STAT1, this aim will uncover a heretofore unknown
signaling pathway that drives immunogenic macrophage programming involving the cytoplasmic tail of ICOSL.

## Key facts

- **NIH application ID:** 10005022
- **Project number:** 5F30CA243205-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Emma Kurz
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,992
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005022

## Citation

> US National Institutes of Health, RePORTER application 10005022, ICOSL Signaling in Macrophages Promotes Anti-Tumor Immunity (5F30CA243205-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10005022. Licensed CC0.

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